Allergic diseases affect well over 25% of the population in industrialized nations. They account for a substantial amount of morbidity and in some cases, mortality. These diseases include asthma, allergic rhinitis, atopic dermatitis, food allergy, drug allergy, anaphylaxis, and urticaria, amongst others. Despite the development of new pharmaceutical agents like inhaled corticosteroids, non-sedating antihistamines and leukotriene inhibitors, the most prevalent allergic disorders, namely, asthma and allergic rhinitis, continue to represent debilitating and costly conditions, In the U.S. alone, 40 million people suffer from allergic rhinitis at a cost of over $7 billion dollars. Asthma sufferers number over 17 million and account for approximately $10.7 billion dollars in health care-related expenditures.
The lynchpin of allergic inflammation is the IgE immunoglobulin molecule. For some time, it has been appreciated that IgE antibodies specific for environmental allergens bind to specialized receptors on target cells, called mast cells, that are distributed along the tissues that line the respiratory tract, gastrointestinal tract, nerve endings, and blood vessels. The encounter of such IgE-sensitized mast cells with specific allergens, e.g. ragweed pollen, bee venom, or latex protein, triggers the release of many chemical mediators. These, in turn, engender a characteristic pattern of allergic inflammation in the involved tissues and cause allergic symptoms like congested runny nose, itchy eyes, wheezing, shortness of breath, and, in the worst case scenario, cardiovascular collapse and death.
In the past decade, extraordinary gains have been made in our understanding of the cellular and molecular basis of IgE production and regulation of the allergic inflammatory response. It is now appreciated that B cells that give rise to IgE secreting plasma cells do so only with the assistance of so-called helper T cells that also react with the offending allergen. This assistance is provided by a physical interaction of the allergen specific T and B cells and the provision of soluble factors from the T cells to the B cells that foster their maturation into IgE-secreting plasma cells. Such helper T cells are called TH2 cells. By contrast, TH1 cells, another population of helper T cells, inhibit the activity of allergy-promoting TH2 cells by secreting a myriad of counter-regulatory molecules that interfere whit TH2 cell function. It appears that the balance of helper activity in allergic individuals is skewed towards the TH2 cells, thus favoring the development of an IgE/allergic inflammatory response.
Based on this overall mechanistic understanding of the allergic inflammatory response, a number of strategies have emerged to treat allergic diseases like allergic rhinitis and asthma. Several are directed at interdicting the activity of allergen-specific TH2 cells. These include direct inhibition of TH2 cell activity or augmentation of allergen-specific TH1 cell activity with resultant indirect inhibitory action of TH2 cells. Others interfere with IgE-mediated allergic inflammation, e.g., prevention of IgE binding the mast cell receptors and interference with the biochemical signals in allergen-triggered IgE-sensitized mast cells that lead to the release of inflammatory mediators. All of these approaches have shown efficacy in short-term animal models of allergic inflammation including asthma. To date early clinical trials have provided some evidence for clinical efficacy of some of these approaches but their addition to the clinical armamentarium may be limited by toxicity and/or unacceptable expense.
There remains a need for effective compositions and methods for preventing and treating IgE mediated allergic disease and conditions.